Alpha-pyrrolidinomethyl valero and caprophenones



United States Patent 3,252,996 ALPHA-PYRROLIDINOMETHYL VALERO AND CAPROPHENONES Charles Ferdinand Huebner, Chatham, N.J., assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed Sept. 14, 1964, Ser. No. 396,352 12 Claims. (Cl. 260-3265) This is a continuation-in-part of my application Serial No. 227,712, filed October 2, 1962, now abandoned, which in turn is a continuation-in-part application of my application Serial No. 153,707, filed November 20, 1961, now Patent 3,151,124.

The present invention concerns amino-ketones, or salts thereof. More especially, the invention relates to compounds of the formula:

C Hz-(C nH2u-i-1) in which Am is N,N-di-lower alkyl-amino or l-N,N- alkylene-imino, in which alkylene has from four to six carbon atoms, and the group of the formula is alkyl having from two to four carbon atoms, and the acid addition salts thereof, as well as process for the manufacture of these compounds.

The group of the formula (C I-l representing an alkyl group having from two to four carbon atoms (the letter n stands for an integer from 2 to 4 inclusive), is particularly ethyl or n-propyl, as well as isopropyl, n-butyl, isobutyl, secondary butyl and the like.

An N,N-di-lower alkyl-amino representing the group Am is above all N,N-dimethylamino, as well as N-ethyl-N- methylamino, N,N-'diethylamino, N,N-di-n-propylamino and the like. An N,N-alkylene-imino group, in which alkylene has from four to six carbon atoms, is usually l-pyrrolidino, as well as l-piperidino, 2-methyl-1-piperidino, 1-N,N-(l,6-hexylene)-imino and the like.

Salts of the compounds of this invention are acid addition salts, such as the pharmaceutically acceptable, nontoxic acid addition salts with inorganic acids, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like, with organic carboxylic acids, e.g. acetic, propionic, glycolic, lactic, succinic, maleic, hyd-roxymaleic, fumaric, :malic, tartaric, citric, glucuronic, benzoic, salicylic, 2-acetoxybenzoic, pamoic, nicotinic isonicotinic acid and the like, or with organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic, Z-hydroxyethane sulfonic, benzene sulfonic, p-toluene sulfonic, naphthalene 2-sulfonic acid and the like. Other acid addition salts may be used \as intermediates, for example, for the preparation of other acid addition salts, such as those having pharmaceutically acceptable properties, or in the purification of the free compound, or may be used for identification or characterization purposes. Acid ad dition salts which are primarily used for the latter, for example, certain inorganic acids, e.g. perchloric acid and the like, with acidic organic nitro compounds, e.g. picric, picrolonic, flavianic acid and the like, or with metal complex acids, e.g. phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like.

The compounds may be in the form of mixtures of isomers or of the separated isomers.

The compounds of this invention produce an increase in coordinated motor activity in the unanesthetized dog, which effect is of considerable duration. They also antagonize sedation induced by administering tranquilizer-type sedatives; the antagonism becomes evident a Patented May 24, 1966 "ice short period after administration and is noticable over an appreciable period. In view of these stimulating effects, the compounds of this invention are useful stimulating agents to counteract excessive fatigue, lack of concentration, depressive states and the like, as well as in the treatment of barbiturate poisoning, or for the shortening of the recovery time after anesthesia. It has also been found, that the compounds of this invention have less toxic characteristics than known stimulating compounds.

The compounds of this invention are also useful as intermediates for the preparation of other pharmacologically active compounds. Upon reduction of the carbonyl group and, if desired, conversion of a resulting hydroxyl group into an esterified hydroxyl group according to methods described below, they are converted into compounds of the following formula:

in which Am and the radical of the formula (C H have the previously-given meaning, and R is hydrogen or the acyl radical of an organic carboxylic acid, or salts thereof. The group R in the above formula, which stands usually for hydrogen, may also be the acyl radical of a lower aliphatic carboxylic acid, such as, for example, a lower alkyl carbonic acid, e.g. methyl carbonic, ethyl carbonic acid and the like, carbamic acid, an N-lower alkyl-carbamic acid, e.g. N-methyl-ca-rbarnic, N-ethylcarbamic acid and the like, or, above all, a lower alkanoic acid, e.g. acetic, propionic, butyric, pivalic acid and the like, as well as any other suitable organic carboxylic acid, e.g. cyclohexane carboxylic, fi-cyclopentyl propionic, benzoic, 3,4,5-trimethoxybenzoic, phenylacetic, nicotinic, isonicotinic acid and the like. These compounds also have stimulating properties, and, in addition, show analgesic effects; they are, therefore, useful as stimulants and/or as analgesics for the relief of pain.

Reduction of the carbonyl group is carried out according to conventional methods, for example, by treatment with a hydride reducive reagent, such as lithium aluminum hydride, sodium borohydride and the like, which reagents may be used in the presence of an activator, such as aluminum chloride and the like. Other methods suitable for the conversion of the carbonyl group into a carbinol group are, for example, treatment with certain metal lower alkoxides, e.g. aluminum isopropoxide and the like, which are used according to the Meerwein-Ponndorf-Verley method (A. L. Wilds, Organic Reactions, Volume 2, page 178, Wiley, 1944), reaction with certain metals in the presence of an acid or a base, for example, iron in the presence of aqueous acetic acid, zinc in the presence of sodium hydroxide in ethanol and :the like, catalytic hydrogenation using Raney nickel, palladium preparations and the like, as the catalysts, or any other suitable reagent. The reduction of the carbonyl to the carbinol group may also be achieved by electrolytic reduction.

Particularly useful as central nervous system stimulants are the compounds of the formula:

in which the letter m stands for the integer 1 or 2, or acid addition salts thereof, either in the form of their racemates or their optically active antipodes.

The compounds of this invention are prepared acin which the group of the formula (C,,H has the previously given meaning, with an amine of the formula HAm, in which Am has the previously-given meaning, or a salt thereof, in the presence of formaldehyde or a reactive derivative thereof, and, if desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, converting a resulting compound into a salt thereof, and/ or, if desired, separating a mixture of isomers into the single isomers.

The above reaction of the starting material with the amine in the presence of formaldehyde or a reactive derivative thereof is carried out according to the procedure known as the Mannich Reaction, which is described, for example, in detail by F. F. Blicke in Organic Reactions, volume 1, page 303 (Wiley, 1942). The salt of an amine of the formula HAm is an acid addition salt, particularly .the salt with a mineral acid, e.g. hydrochloric, hydrobromic, sulfuric acid and the like. Reactive derivatives of formaldehyde are those furnishing formaldehyde under the conditions of the reaction; such derivatives are, for example, polymeric derivatives of formaldehyde, e.g. paraformaldehyde, trioxane and the like, acetals of formaldehyde with lower alkanols, e.g. dimethoxymethane, diethoxymethane and the like, hexamethylenetetramine, or any other suitable formaldehydefurnishing reagent. The reaction is preferably carried out in the presence of an inert solvent, for example, a lower alkanol, e.g. ethanol and the like, preferably at an elevated temperature, and, if necessary, in the presence of a small amount of an acid, such as a mineral acid, e.g. hydrochloric, sulfuric acid and the like, and/or, in a closed vessel, and/or, in the atmosphere of an inert gas, e.g. nitrogen.

The starting material are known and can be prepared according to per se conventional methods.

The compounds of this invention are also prepared by reacting a compound of the formula:

in which the group of the formula (C H has the previously-given meaning, and X is a reactive esterified hydroxyl group, with an amine of the formula HAm, in which Am has the above-given meaning, or a salt thereof, and, if desired, carrying out the optional steps.

The reactive esterified hydroxyl group X, stands primarily for halogeno (representing a hydroxyl group esterified with a hydrohalic acid), e.g. chloro, bromo and the like, as well as an organic sulfonyloxy group, e.g. p-toluene sulfonyloxy and .the like. The above reaction between the reactive ester and the amine is carried out according to per se conventional methods, preferably by maintaining an excess of the amine, which may simultaneously serve as a base to neutralize the generated acid. The latter may also be achieved by adding another alkaline reagent, e.g. sodium carbonate, potassium carbonate and the like. The reaction is preferably completed at an elevated temperature, if desired, in the presence of an inert solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol and the like, or any other suitable diluent, and/or, in a closed vessel, and/or in the atmosphere of an inert gas, e.g. nitrogen.

The starting materials may be prepared accordance to methods known per se, for example, by introducing into the a-POSltiOIl of a compound of the formula:

in which the group of the formula (C H has the previously-given meaning, a carbon-lower alkoxy group, e.g. carbethoxy and the like (for example, by treatment of an alkali metal compound of the ketone with a lower alkyl orthoformate, e.g. ethyl orthoformate and the like) or a hydroxy-methylene group (for example, by treating an alkali metal compound of the ketone with a lower alkyl formate, e.g. ethyl formate and the like). resulting compound, the carbo-lower alkoxy (if necessary, after hydrolysis to the free carboxyl group) or the hydroxy-methylene group is then converted into a hydroxy-methyl group by reduction, for example, by treat ment with a hydride reagent, e.g. lithium aluminum hydride and the like, or any other suitable reduction procedure, such as catalytic hydrogenation, electrolytic reduction and the like. The hydroxy-methyl group may also be introduced directly into the tat-position of the above starting material, for example, by reacting the latter with formaldehyde or a formaldehyde-furnishing.

reagent, e.g. paraforrnaldehyde and the like, in the presence of a suitable base, e.g. sodium carbonate and the like. The free hydroxyl group of the hydroxy-methyl portion of the resulting compound is then replaced by the desired reactive esterified hydroxyl group, for example, by halogeno (e.g. by treatment with a thionyl halide, e.g. thionyl chloride and the like, or a phosphorous halide, e.g. phosphorous tribromide and the like), or by an organic sulfonyloxy group (e.g. by esterification with an organic sulfonic acid halide, e.g. p-toluene sulfonic acid chloride and the like, preferably in the presence of a base, e.g. pyridine and the like).

The compounds of this invention may also by prepared, for vexample, by reacting a metal reagent of the formula:

in which M stands for the cation of certain metals of the group I-A of the Periodic System, or particularly for the cation of the formula HalMet in which Met stands for certain metals of the group lI-A of the Periodic System, and Hal stands for halogeno, with a compound of the formula:

in which Am and the group of the formula (C,,H have the previously-given meaning, and each of the groups R,, and R stands for hydrogen or an organic substituent, and, if desired, carrying out the optional steps.

A cation of metals of the group I-A of .the Periodic System, represented by M is that of certain alkali metals, particularly lithium, as well as sodium. Preferably, M is the group HalMet which stands primarily for Hal-Mg, in which Hal is halogeno, having an atomic weight greater than 35, e.g. chloro, bromo and the like. These metal reagents are known or are prepared according to known methods.

In the acid amide starting materials, each of the groups R and R which are preferably hydrogen, may also be an organic radical, particularly lower alkyl, e.g. methyl,

ethyl and the like. The above reaction is carried out according to known methods, especially in the presence of an inert solvent, ifnecessary, at an elevated temperature and/or in the atmosphere of an inert gas, e.g. nitrogen.

Ina.

The starting materials used in the above reaction are prepared according to known methods, for example, by reacting a compound of the formula:

in which the group of the formula --(C,,H has the previously-given meaning, and R is lower alkyl, with an amine of the formula HAm, in which Am has the abovegiven meaning, and converting the esterified carboxyl group into the desired amide group by treatment with ammonia, a primary amine or a secondary amine; these reactions are carried out according to known methods.

In view of the fact that the compounds of the formula:

in which Am and the group of the formula -(C,,H have the previously-given meaning, or a salt thereof, may be prepared independently from the compounds of this invention having the formula:

Hz-(C 1121144) in which Am and the group of the formula -(C H have the previously-given meaning, they may also serve as starting materials for the preparation of the latter; they can be converted into the latter by oxidizing the carbinol group into a carbonyl group, and, if desired, carrying out the optional steps.

Oxidation of the carbinol into the carbonyl group is carried out according to known methods, for example, by treatment with an oxidation reagent containing hexavalent chromium, e.g. potassium dichromate, chromium trioxide (for example, in the form of the complex with pyridine) and the like, with aluminum tertiary butanolate according to the Oppenauer oxidation reaction as described, for example, by C. Djerassi, Organic Reactions, volume 6, page 207 (Wiley, 1951), or any other oxidation method suitable for the conversion of a carbinol into a carbonyl group.

The starting materials used in the above procedure are prepared according to methods, which are independent from the ketone compounds of this invention. For example, a compound of the formula:

C Hz (C Ham-1) in which R, X,,, and the radical of the formula n 2n+1) have the previously-given meaning, may be reacted with an amine of the formula H-Am, in which Am has the previously-given meaning; this reaction is carried out according to the previously-described method. The starting materials used in the reaction may be obtained, for example, by converting in a compound having the formula:

in which the group of the formula (C H have the above-given meaning, and Y stands for a group of the formula CH -X in which X, is a reactive esterified hydroxyl group, or a carbinol group or a group capable of being converted into a carbinol group (such as a carbolower alkoxy group, e.g. carboethoxy and the like, a hydroxymethylene group and the like), the carbonyl group adjacent to the phenyl group into a carbinol group (for example, according to one of the reduction methods previously described), and, if necessary, converting in a resulting compound, in which Y stands for a group capable of being converted into a carbinol group, such group into a carbinol group (for example, by one of the reduction methods previously-described), and/ or, if necessary, converting in a resulting compound, in which the group Y is a carbinol group, such carbinol group into the group of the formula CH -X,,, in which X, is a reactive esterified group (for example, by treatment with a thionyl halide, e.g. thionyl chloride and the like, or with an organic sulfonyl halide, e.g. chloride and the like, according to the previously-shown procedure), and, if desired, converting in a resulting compound the secondary caribnol group adjacent to the phenyl group into an esterified carbinol group (according to known methods), for example, by treatment with an acid halide, e.g. chloride and the like, or an acid anhydride, if necessary, in the presence of a base, e.g. pyridine and the like.

The starting materials used in the above oxidation procedure for the preparation of the ketone compounds of this invention may also be prepared, for example, by converting in a compound having the formula:

in which Am and the group of the formula (C,,H have the previously-given meaning, and Z stands for a carbinol group, an esterified carbinol group or a carbonyl group, the carbonyl group of the formula 0 0 into methylene, and, if necessary, converting in a resulting compound having a carbonyl group, such carbonyl group into a carbinol group.

A carbonyl group of the formula C=O represents the carbonyl portion of the amide grouping, which is converted into a methylene group according to known methods, for example, by treatment with a suitable hydride reagent, e.g. lithium aluminum hydride and the like. In starting materials, in which Z stands for a carbonyl group, such group may be reduced simultaneously to the desired carbinol group.

The starting materials used in the above reaction are prepared according to known methods, such as those previously-shown. If desired, a carbonyl group Z is converted into the carbinol group using one of the previously described reduction methods, which do not attack the carbonyl of an amide grouping, such as, for example, treatment with hydrogen in the presence of a suitable catalyst, or with certain metal lower alkoxides, e.g. aluminum isopropoxide and the like (these methods have been previously outlined).

The carbinol starting materials used in the above oxidation procedure may also be prepared, for example, by reducing the aliphatic carbon-to-carbon double bond in a compound of the formula:

C Hr-(C n Zu-H) in which Am, Z and the group of the formula C Hz- (C nHzm 1) I in which the group of the formula (C,,H has the previously-given meaning, a hydroxymethylene group according to the previously-described method (for example, by reacting an alkali metal compound of the ketone with a lower alkyl formate), and reacting the resulting compound having a hydroxy-methylene group in a-POSitiOIl to the carbonyl group, with an amine of the formula H-Am, in which Am has the previously-given meaning, and, if desired, converting the carbonyl group adjacent to the phenyl portion into a carbinol group (for example, by reduction according to the Meerwein-Ponndorf-Verley method), and the latter into an esterified carbinol group by esterification (for example, as shown hereinbelow).

The carbinol compounds of the above formula may also be prepared by reacting a compound of the formula:

in which M has the previously-given meaning, with an aldehyde of the formula:

in which Am and the group of the formula (C H have the previously-given meaning. The above reaction is carried out according to the previously described method; the starting materials are prepared by adapting known methods to the appropriate starting materials.

Depending on the conditions used, the compounds of this invention are obtained in the form of the free bases or the salts.

A resulting acid addition salt is converted into the free base, for example, by reacting it with a suitable hydroxyl ion exchange preparation, or with an alkaline reagent, such as a metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, a metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate and the like, ammonia or any other suitable basic reagent.

An acid addition salt is converted directly into another acid addition salt, for example, by reacting it with a suitable anion exchange preparation. Furthermore, a salt with an inorganic acid may be reacted with a metal, e.g. sodium, barium, silver and the like, salt of an acid, preferably in the presence of a solvent, in which a resulting inorganic compound is insoluble and is thus removed from the reaction medium. For example, a resulting hydrobrornide may be converted into the maleate by treatment with the monosodium salt of maleic acid in a suitable diluent.

A free compound may be converted into an acid addition salt by reaction with one of the inorganic or organic acids described hereinbefore, for example, by treating a solution of the base in a suitable solvent with the acid or a solution thereof and isolating the desired salt. The latter may also be obtained by reacting the free compound with a suitable anion exchange preparation. Salts may be obtained in the form of hydrates or may contain solvent of crystallization formation of the salts.

Compounds of this invention may be obtained as mixtures of isomers, which may be separated into the individual isomers. For example, racemates of the compounds of this invention may be resolved into the optically active dand lforms according to procedures used for the resolution of racemic compounds. For example, a solution of the free base of a racemic d,l-cmpound in an inert solvent may be treated with one of the optically active forms of an acid having at least one asymmetric carbon atom. Especially useful as optically active forms of salt-forming acids having an asymmetric carbon atom are D-tartaric (l-tartaric) and L-tartaric (d-tartaric) acid, as well as the optically active forms of di-benZoyl-tartaric, di-o-tartaric, malic, mandelic, camphor -sulfonic, quinic acid and the like. A resulting mixture of salts is then separated into the single salts, and,

if desired, the isolated salt may be converted into the optically active base according to known methods, such as those mentioned hereinabove; the optically active base may then be converted into its acid addition salts.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees Centigrade.

Example 1 A mixture of 78 g. of valerophenone, 5.38 g. of pyrrolidine hydrochloride, and 19.5 g. of paraformaldehyde in ml. of ethanol containing 1 ml. of concentrated hydrochloric acid is refluxed for twelve hours. The solvent is then evaporated, the residue is taken up in water, and the aqueous solution, after being extracted with diethyl ether, is made basic with aqueous ammonia. The organic material is extracted with diethyl ether, and the organic solution is dried over magnesium sulfate and evaporated. The residue is distilled to yield the cc-( l-pyrrolidino) -methyl-valerophenone of the formula:

which is collected at B.P. 132136/0.7 mm.; yields: 49 g. Other compounds prepared according to the above procedure are, for example,

a N,N diethylaminomethyl valerophenone, B.P. 100- 102/ 0.15 mm., which is prepared by reacting valerophenone with N,N-diethylamine hydrochloride in the presence of paraformaldehyde;

a N,N dimethylaminomethyl valerophenone, which is prepared by reacting valerophenone with N,N-dimethylamine in the presence of paraformaldehyde and which is converted into its hydrochloride salt, M.P. 157158, after recrystallization from a mixture of ethanol and diethyl ether;

a-(l-piperidino)-methyl-valerophenone, B.P. l23125/ 0.3 mm., which is prepared by reacting valerophenone with piperidine hydrochloride in the presence of paraformaldehyde,

a [1-N,N-(1,6-hexylene)-imino]-methyl-valerophenone, B.P. 132l33/0.l5 mm., which is prepared by reacting valerophenone with N,N-(l,6-hexylene)-imine in the presence of paraformaldehyde, and the like.

The above compounds may be used as starting materials for the preparation of the corresponding carbinol compounds, for example, according to the following procedure: To a solution of 11.0 g. of a-(1-pyrrolidino)- methyl-valerophenone in 100 ml. of ethanol is added in small portions 4.75 g. of sodium borohydride. The reaction mixture is refluxed for four hours; the solvent is evaporated and the residue is treated with water. The organic material is extracted with diethyl ether, the organic solution is dried over magnesium sulfate and evaporated. The residue is distilled to give the l-phenyl-2- (l-pyrrolidino)-methyl-l-pentanol, which boils at 128- 130/0.5 mm.; yield: 6.0 g.

Upon treatment of 1-phenyl-2-(pyrrolidino)-methyl-1- pentanol with propionic acid anhydride in the presence of pyridine, the l phenyl 2 (1-pyrrolidin0)-methyl-lpropionyloxy-pentane can be obtained.

Example 2 To a solution of 66.0 g. of u-(l-pyrrolidino)-methylvalerophenone in diethyl ether is added an excess of a 9 7.5 N solution of hydrogen chloride in ethanol. The resulting precipitate is filtered off, washed with diethyl ether and recrystallized from ethanol, to yield the m-(lpyrrolidino)-methyl-valerophenone hydrochloride, M.P. 141144.

Example 3 A mixture of 17.6 g. of caprophenone, 10 ml. of pyrrolidine, 17 ml'. of 6 N ethanolic hydrogen chloride, 5.9 g. of paraformaldehyde and 20 ml. of ethanol is refluxed for twelve hours. The solvent is evaporated and the residue is taken up in 100 ml. of water; the insoluble material is filtered off and the aqueous solution is made basic with aqueous ammonia. The organic material is extracted with diethyl ether, the organic solution is separated, dried and evaporated, and the residue is distilled to yield the a-(l-pyrrolidino) -methyl-caprophenone of the C HzCH2- H2 a B.P. 168-172/ 1.0 mm., which is converted into its hydrochloride, M.P. 1414 44 after recrystallization from ethanol, according to the procedure described in Example 2.

The a-(l-pyrrolidino)-rnethyl-caprylophenone is obtained by reacting caprylophenone with pyrrolidine and paraformaldehyde in the presence of hydrochloric acid and ethanol according to the above procedure.

Example 4 To a solution of 8.94 g. of (l)-0,0-dibenzoyl-tar taric acid ([a]- =110.92i2 in methanol) in 180 ml. of acetone is added 6.0 g. of a-(l-pyrrolidino)-methyl-valerophenone. The mixture is stirred at room temperature for 21 hours and then evaporated to yield a white gummy material. The latter is dissolved from a mixture of methanol and water; the solution is allowed to stand at room temperature for several hours, whereupon the crystalline salt precipitates and is filtered off; yield: 4.88 g.; M.P. 98107; [u] =76.28 (in methanol). The salt is suspended in water, the mixture is made basic with ammonium hydroxide, and the solution is extracted with diethyl ether. The organic solution is washed with water until the washings are neutral, dried over magnesium sulfate and evaporated to yield 2.0 g. of the (l)-u-(1-pyrrolidino)-methyl-valerophenone, [a] =5.68 (in methanol).

The above base is dissolved in diethyl ether and an equimolar amount of a 12 N solution of hydrogen chloride in ethanol is added. A total of 0.9 g. of the crystalline (l)-a-(l-pyrrolidino)-methyl-valerophenone hydrochloride is obtained, M.P. 142-145"; [a] =-18.12 (in methanol).

Example 5 To a solution of 53.8 ml. of pyrrolidine in 127 ml. of a 6 N ethanol solution of hydrogen chloride are added 57 g. of dimethoxymethane, 100.0 g. of valerophenone, 1.1 ml. of concentrated hydrochloric acid and 25 ml. of ethanol. The reaction mixture is refluxed for twelve hours; the solvent is then evaporated under reduced pressure, and the residue is diluted with water. The unreacted valerophenone is extracted with diethyl ether; the aqueous layer is made basic with ammonium hydroxide and the organic basic material is extracted with diethyl ether. The organic solution is dried over sodium sulfate and evaporated to yield the u-(1-pyrrolidino)- methyl-valerophenone, which is purified by distillation and collected at 121-124/0.07 mm.

Example 6 The crude whydroxymethyl-valerophenone p-toluene sulfonic acid ester (prepared according to the procedure described herein below) and 20.0 g. of pyrrolidine in ml. of ethanol are refluxed, and the solvents are then evaporated under reduced pressure; the residue is treated with an aqueous solution of ammonia and the organic material is extracted with diethyl ether. The organic solution is separated, dried over sodium sulfate and evaporated. The residue is distilled, B.P. 132 136/0.7 mm., to yield the desired CAI-pyrrolidine)- methyl-valerophenone, which is converted into its hydrochloride, M.P. 141-144, according to the procedure de scribed in Example 2.

The starting material used in the above procedure is prepared as follows: A suspension of 50.0 g. of valerophenone and 11.0 g. of paraformaldehyde in 500 ml. of water containing 1.0 g. of sodium carbonate is stirred for 48 hours. The solid u-hydroxymethyl-valerophenone is filtered off and 25.0 g. of this material is dissolved in 100 ml. of pyridine; the solution is treated with 30.0 g. of p-toluene sulfonic acid chloride. After standing for 24 hours, the mixture is poured into ice water and the ot-hydroxymethyl-valerophenone p-toluene sulfonic acid ester is filtered off.

In the above procedure, the a-hydroxymethyl-valerophenone p-toluene sulfonic acid ester may be replaced by a-chloromethyl-valerophenone or by a-bromomethylvalerophenone; by refluxing the latter with pyrrolidine in the presence of ethanol, they are converted into the desired a-(l-pyrrolidino)-methylvalerophenone. The starting materials are prepared by reacting the u-hydroxymethyl-valerophenone with one mol of thionyl chloride in refluxing chloroform or with phosphorous tribromide, pouring the resulting compound into ice water and isolating the desired a-halogeno-methyl-valerophenone compound.

Example 7 To a mixture of 25.0 g. of 1-phenyl-2-(l-pyrrolidino)- methyl-n-pentanol in 100 ml. of pyridine is added slowly 12.2 g. of Sarretts reagent (chromium trioxide-pyridine complex) while externally cooling to maintain room temperature. After twelve hours, the pyridine is distilled off under reduced pressure; the residue is diluted with water and treated with an aqueous solution of ammonium hydroxide. The organic material is extracted, the organic solution is separated, dried and evaporated, and the residue is distilled to yield the u-(l-pyrrolidine)-rnethylvalerophenone, B.P. 132136/O.7 mm., which is converted into its crystalline hydrochloride, M.P. 141-144", according to the method described in Example 2.

The starting material used in the above procedure is prepared as follows: A solution of 100.0 g. of a a-(npropyl)-acrolein in 500 ml. of absolute ethanol is saturated with hydrogen chloride while maintaining a temperature of 0. After two days standing at room temperature, the solvent is removed and the ec-chloromethyh valeraldehyde diethylacetal is distilled under reduced pressure. A mixture of 50.0 g. of ct-chloromethyl-valeraldehyde and 35.0 g. of pyrrolidine in 200 ml. of ethanol is refluxed for twelve hours. The solvent is removed under reduced pressure and the residue is dissolved in water; the aqueous mixture is made basic with ammonium hydroxide and is extracted with diethyl ether. The desired a-(l-pyrrolidino) methyl valeraldehyde diethylacetal is purified by distilling the residue of the diethyl ether extract.

A solution of 50.0 g. of a-(1-pyrrolidino)-methyl-valeraldehyde diethyla-cetal in 250 ml. of 2 N aqueous hydrochloric acid is allowed to stand for three days. The solution is then made basic and the a-(1-pyrrolidino)-methyl-valeraldehyde is extracted with 200 ml. of anhydrous diethyl ether. After drying over magnesium sulfate, this ether solution is added to a Grignard reagent, prepared from 34.0 g. of bromobenzene and 5.5 g. of magnesium in 200 ml. of diethyl ether. After refluxing for two hours, the reaction mixture is cooled and treated with ml. of a saturated aqueous solution of ammonium chloride; the organic layer is separated and washed with dilute aqueous hydrochloric acid. The combined acidic washings are rendered basic with aqueous ammonia; the organic material is extracted wtih diethyl ether and the desired 1phenyl-2-(l-pyrrolidino)-methyl-n-pentanol is isolated by separating, drying and evaporating the organic solution and distilling the residue; the desired product boils at l28l30/ 0.5 mm., and is identical with the product obtained according to the procedure of Example 1.

Example 8 To a Grignard reagent, prepared by reacting 62.0 g. of bromobenzene and g. of magnesium in 500 ml. of diethyl ether and initiating the reaction by adding a small amount of crystalline iodine, is added a diethyl ether solution of o-(l-pyrrolidino)-methyl-valeric acid amide as prepared according to the procedure described below. The reaction mixture is refluxed for twelve hours, and is then cooled and treated dropwise with 200 ml. of a saturated aqueous solution of ammonium chloride. The diethyl ether solution is separated, and extracted with dilute aqueous hydrochloric acid. The combined aqueous extracts are made basic with an aqueous solution of ammonia, and the organic material is extracted with diethyl ether. The organic solution is separated, dried over sodium sulfate and evaporated. The residue is distilled, B.P. 132-l36/0.7 mm., to yield the desired u-(l-pyrrolidino)-methyl-valerophenone, which is converted into its hydrochloride, M.P. 141- -144, according to the procedure described in Example 2.

The starting material used in the above procedure may be prepared as follows: To a solution of 50.0 g. of methyl a-propylacrylate in 200 ml. of ethanol containing 1 ml. of a 30 percent solution of benzyl trimethyl ammonium hydroxide, is added 28.0 g. of pyrrolidine while externally cooling. After reacting for six hours at room temperature, the reaction mixture is saturated with dry ammonia and is allowed to stand at room temperature for one week. The solvent is distilled off under reduced pressure to yield the crude a-(1-pyrrolidino)-methyl-valeric acid amide, which is purified by dissolving it in 100 ml. of anhydrous diethyl ether, washing the organic solution twice with water and drying over magnesium sulfate, and used without further isolation.

Example 9 The compounds of this invention may be used in the form of compositions for enteral or parenteral use, which contain the new compounds in admixture with an organic or inorganic, solid or liquid carrier. These preparations are manufactured according to known methods, and car rier materials are employed which do not react with the new com-pounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talcum, vegetable oils, benzyl alcohol, gums, tragacanth, propylene glycol, polyalkylene glycols or any other carrier useful for the preparation of compositions. The latter may be in solid form, for example, as capsules, tablets, and the like, or in liquid form, for example, as solutions, suspensions, emulsions, and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying, coloring, flavoring agents, and the like, salts for varying the osmotic pressure, buffers, etc. They may also contain, in combination, other useful substances.

Compositions included within the scope of this invention contain from about one percent to about fifty percent of a compound of the formula:

in which Am and the group of the formula --(C,,H have the previously-given meaning, or a pharmaceutically acceptable non-toxic acid addition salt thereof, together with a carrier. For example, compositions for oral administration contain from about 0.005 g. to about 0.05 g., preferably from about 0.01 g. to about 0.03 g. of one of the above compounds, especially of a compound of the formula:

0 CHz-C H2 in which the letter m has the previously-given meaning, particularly of a-(1-pyrrolidino)-methyl-valerophenone, either in the form of a racemate or an optically active antipode or a pharmaceutically acceptable, non-toxic acid addition salt thereof, together with a carrier.

Tablets containing 0.02 g. of a-(1-pyrrolidino)-methylvalerophenone hydrochloride, are prepared as follows (for 1,000,000 tablets) Ingredients:

a-(l pyrrolidino)-methyl-valerophenone hydrochloride g 20,0000 Tragacanth BC g 4,000.0 Lactose g 123,9800 Confectioners Sugar g 30,0000 Color D & C Orange No. 3 g 20.0 Talcum g 10,000.0 Corn starch g 10,0000 Magnesium stearate g 2,000.0 Anhydrous alcohol 3A m1 10,000.0 Purified water ml 10,0000

The a-(l-pyrrolidino)-methyl-valerophenone hydrochloride and the tragacanth are passed through a Fitzpatrick mill, set at low speed, knives forward and using a No. 1 Type A screen. The D & C Orange No. 3 is triturated with 3,000 g. of lactose, previously-screened through a No. 16 sieve. 120,980 g. of lactose is screened through a No. 16 sieve and is placed into a mixer; the color triturate, the mixture of the a-(1-pyrrolidino)-methylvalerophenone hydrochloride and the tragacanth, and the confectioners sugar (previously passed through a No. 16 screen) are added in this order. Mixing is maintained at high speed (68 rpm.) for twenty minutes; 20,000 ml. of 50 percent alcohol 3A is added, and mixing is continued at the same speed for thirty minutes to form the granules; additional 50 percent alcohol 3A is added, if needed.

The wet granules are passed through a Fitzpatrick mill set at low speed, knives forward and using a No. 4 Type A screen. The product is spread on trays and dried for about two and one-half hours at 433 using circulating dehumidified air; the moisture content of the dried product is between about 2.5 percent minimum and 3 percent maximum. The granules are then passed through a Fitzpatrick mill, set at medium speed, knives forward and using a No. 2 Type A screen. The granules are placed into a mixer and the talcum, corn starch and magnesium stearate used as the lubricants are added through a No. 16 screen. Mixing is maintained for twenty minutes, at high speed, and the granules are compressed into tablets weighing 0.2 g. each, using 10/ 32 inch shallow concave punches.

Capsules containing 0.01 g. of (l)-a-(1-pyrrolidino)- methyl-valerophenone hydrochloride, are prepared as follows (for 10,000 capsules):

Ingredients: G. (1)-a-(1-pyrrolidino) -methyl valerophenone hydrochloride 100.0 Corn starch 150.0 Magnesium stearate 25.0 Lactose 3225.0

The ingredients are thoroughly mixed, and the mixture is passed through a No. 30 screen. After mixing for an additional thirty minutes, the resulting product is filled on in which Am is 1-N,N-alkylene-imino, in which alkylene has four carbon atoms, and the group of the formula --(C,,H is alkyl having from two to four carbon atoms, and an acid addition salt thereof.

2. A compound of the formula:

in which the letter m is an integer from 1 to 2.

3. An acid addition salt of a compound of the formula:

in which the letter m is an integer from 1 to 2.

4. u-( l-pyrrolidino)-methyl-valerophenone.

5. An acid addition salt of u-(l-pyrrolidino)-methylvalerophenone.

6. a-(l-pyrrolidino)-methyl-valerophenone hydrochlo ride.

7. (l -oc-( l-pyrrolidino -rnet'hylvalerophenone.

8. An acid addition salt of (l)-a-(l-pyrrolidino)-methyl-valerophenone.

9. (l)-a-(l-pyrrolidino)-methyl-valerophcnone hydrochloride.

10. a-(l pyrrolidino)-methyl-caprophenone.

11. An acid addition salt of a-(l-pyrroiidino)-methylcaprophenone.

12. w(l-pyrrolidino)-methyl-caprophen0ne hydrochloride.

References Cited by the Examiner UNITED STATES PATENTS 1,915,334 6/1933 Salzberg et al. 260--243 2,075,359 3/1937 Salzberg et a1 167-22 2,778,853 1/1957 Schultz et a1 260-590 3,000,946 9/1961 De Stevens 260-5705 NICHOLAS S. RIZZO, Primary Examiner. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA:
 6. A-(1-PYRROLIDINO)-METHYL-VALEROPHENONE HYDROCHLORIDE. 